WO2014207213A1 - Nouveaux inhibiteurs de la signalisation de la protéine kinase c epsilon - Google Patents

Nouveaux inhibiteurs de la signalisation de la protéine kinase c epsilon Download PDF

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WO2014207213A1
WO2014207213A1 PCT/EP2014/063723 EP2014063723W WO2014207213A1 WO 2014207213 A1 WO2014207213 A1 WO 2014207213A1 EP 2014063723 W EP2014063723 W EP 2014063723W WO 2014207213 A1 WO2014207213 A1 WO 2014207213A1
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alkyl
compound
cancer
diabetic
disorder
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PCT/EP2014/063723
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Johann Hofmann
Thierry Langer
Johannes KIRCHMAIR
Florian RECHFELD
Peter Gruber
Markus BÖHLER
Georg HECHENBERGER
Dorota GARCZARCZYK
Maria N. Preobrazhenskaya
Gennady B. LAPA
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Medizinische Universität Innsbruck
Universität Innsbruck
Gause Institute Of New Antibiotics
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D495/14—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4743—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having sulfur as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • Novel inhibitors of protein kinase C epsilon signaling Novel inhibitors of protein kinase C epsilon signaling
  • the present invention relates to novel inhibitors of protein kinase C epsilon (PKCE) signaling, including in particular the compounds of formula (I) as described and defined herein, pharmaceutical compositions comprising these inhibitors, and their use in the treatment or prevention of disorders such as, e.g., a cardiovascular disorder, cardiac hypertrophy, heart failure, anxiety, pain, chronic pain, migraine, an allergy, an inflammatory disorder, an autoimmune disorder, diabetes, diabetic complications, diabetic retinopathy, diabetic nephropathy, diabetic cardiomyopathy, diabetic neuropathy, cancer, metastatic cancer, drug-resistant cancer, stomach cancer, lung cancer, thyroid cancer, colon cancer, breast cancer, a neurological disorder, Alzheimer's disease, Parkinson's disease, bipolar disorder, stroke, alopecia, or alcoholism.
  • PKCE protein kinase C epsilon
  • PKC Protein kinase C
  • the PKC isozymes can be classified into three groups: i) the conventional isozymes ⁇ , ⁇ , ⁇ , and ⁇ ; ii) the novel isozymes ⁇ , ⁇ , ⁇ , and ⁇ ; and iii) the atypical isozymes ⁇ / ⁇ (mouse/human) and ⁇ .
  • PKC isozymes seem to play important roles in the activation of signal transduction pathways leading to synaptic transmissions, the activation of ion fluxes, secretion, proliferation, cell cycle control, differentiation and tumorigenesis.
  • PKC isozymes are described, e.g. , in: Mochly-Rosen et al., 2012; Sanchez-Bautista et al., 2013; Bohler, 2006; US 2009/0124553; and US 6,376,467.
  • the PKCE isozyme was reported to participate in neoplastic transformation (Gorin et al., 2009), cardiac hypertrophy (Pass et al., 2001 ), protection from ischemic insult (Pass et al., 2001 ; Johnson et al., 1996), nociceptor function (Cesare et al., 1999), macrophage activation (Castrillo et al. , 2001 ), diabetes (Ikeda et al., 2001 ) and in alcohol consumption (Choi et al., 2002).
  • a PKCe isozyme-specific inhibitor would have pharmaceutical potential, e.g., for the intervention in stroke, Alzheimer's disease or pain (Akita, 2008; Shirai et al., 2008).
  • kinase inhibitors interact with the ATP-binding site, which is well conserved among different kinase families, and is even more so within a family. This poses a serious hurdle for the development of isozyme-specific inhibitors, as there are approximately 518 kinases encoded by the human genome (Manning et al., 2002). Although several selective kinase inhibitors have been reported initially, later it turned out that they also inhibit other targets. For example, the marketed drug imatinib mesylate (Gleevec/Glivec) was developed as an inhibitor of the oncoprotein Bcr-Abl.
  • PKCp-selective inhibitors such as ruboxistaurine (Fedorov et al., 2007; Nakamura et al., 2010) and enzastaurine (Chen et al., 2008) are in clinical trials for diabetic retinopathy and cancer, respectively.
  • Rottlerin was described as a specific inhibitor of PKC5.
  • additional modes of action have been observed by now (Soltoff, 2007).
  • Small molecule inhibitors of protein-protein interactions have previously been shown to be useful for pharmacological purposes (Beeley, 2000; Arkin et al., 2004).
  • the present invention provides the compounds of formula (I) as described herein below and in the claims.
  • Structurally related compounds have also been disclosed in: Sanam et al. , 2010; US 201 1 /0077250; WO 2013/033037; CN 102757447 A; Pillai et al., 2010; US 2013/0129677; RU 2371444 C1 ; WO 92/03427; and CAS registry nos. 338433-13-9 and 333330-1 1 -3.
  • the barbituric acid derivative BAS 02104951 has furthermore been disclosed as an inhibitor of PKCe signal transduction in Gruber et al., 201 1 .
  • the present invention provides a compound of the following formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof, for use as a medicament:
  • n is an integer of 0 to 4 (i.e. , 0, 1 , 2, 3 or 4), and each R 1 is independently selected from C 1-4 alkyl, C 2 remedy 4 alkenyl, C 2 . 4 alkynyl, -OH, -0(C 1-4 alkyl), -0(C-,. 4 alkyl)-OH, -0(d_ 4 alkyl)-0(C 1-4 alkyl), -SH, -S(C 1-4 alkyl), -S(C 1-4 alkyl)-SH, or -S(C,. 4 alkyl)-S(d.
  • n is 2, 3 or 4
  • two groups R 1 attached to adjacent carbon atoms are mutually linked to form a group -0-CH 2 -0-, -0-CH 2 -CH 2 -0- or -0-CH 2 -CH 2 -CH 2 -0-, while the further group(s) R ⁇ if present (i.e. , if n is 3 or 4), is/are independently selected from C,. 4 alkyl, C 2 .
  • n is an integer of 1 to 4 (i.e. , 1 , 2, 3 or 4)
  • one group R is selected from -0(C 1 -4 alkyl), -OH, -0(C 1-4 alkyl)-OH, or -0(d_ 4 alky!-0(d_ 4 alkyl)
  • the remaining group(s) R 1 if present (i.e., if n is 2, 3 or 4), is/are independently selected from d_ 4 alkyl, C 2-4 alkenyl, C 2-4 aikynyl, -OH, -0(Ci_ 4 alkyl), -0(C 1-4 alkyl)-OH, -0(C 1 -4 alkyl)-0(d_ 4 alkyl), -SH, -S(C 1-4 alkyl), -S(C 1-4 alkyl)-SH, or -S(C 1-4 alkyl)-S(C 1 -4 alkyl), -NH
  • n 2 aikyl(C - alkyl), halogen, -CF 3 , or -CN; or, alternatively, n is 2, and the two groups R 1 are attached to adjacent carbon atoms (preferably the same two carbon atoms as in the compounds 1a and 1 b shown below) and are mutually linked to form a group -0-CH 2 -0-, -0-CH 2 -CH 2 -0- or -0-CH 2 -CH 2 -CH 2 -0-.
  • n is 1 and R 1 is selected from -0(C -4 alkyl), -OH, -0(C 1-4 alkyI)-OH, or -0(C 1-4 alkyl)-0(d_ 4 alkyl), wherein it is particularly preferred that R 1 is selected from -OCH 3 or -OCH 2 CH 3 ; or, alternatively, n is 2 and the two groups R 1 are attached to adjacent carbon atoms (preferably the same two carbon atoms as in the compounds 1 a and 1 b shown below) and are mutually linked to form a group -0-CH 2 -0- or -0-CH 2 -CH 2 -0-.
  • R 2 is selected from hydrogen, C 1-4 alkyl, C 2 . 4 alkenyl, C 2 . 4 aikynyl, -OH, -0(C 1 -4 alkyl), -SH, -S(d_ 4 alkyl), -NH 2 , -NH(C 1-4 alkyl), -N(C 1-4 alkyl)(d. 4 alkyl), halogen, -CF 3 , or -CN.
  • R 2 is hydrogen.
  • R 3 is selected from -NH 2 , -NH(C 1-4 alkyl), -N(d.
  • R 3 is -NH 2 , -NH(d_ 4 alkyl), -OH, or -SH. More preferably, R 3 is -NH 2 .
  • X is selected from S, O, N(H), or N(d. 4 alkyl).
  • X is S or O. More preferably, X is S.
  • L is -(CH 2 )i-4-, wherein one -CH 2 - unit comprised in said -(CH 2 ) -4 - is replaced by a group selected from -CO-NH-, -CO-N(d. 4 alkyl)-, -NH-CO-, -N(d_ 4 alkyl)-CO-, -0-, -CO-, -NH-, -N(d_ 4 alkyl)-, -S-, -SO-, or -S0 2 -.
  • L is -(CH 2 ) 1-3 -, wherein one -CH 2 - unit comprised in said -(CH 2 ) 1-3 - is replaced by a group selected from -CO-NH-, -CO-N(d. 4 alkyl)-, -NH-CO-, or -N(d. 4 alkyl)-CO-. More preferably, L is directionally selected from -CO- NH-, -CO-N(d. 4 alkyl)-, -NH-CO-, or -N(d. 4 alkyl)-CO-.
  • L is -CO-NH- or -CO-N(d_ 4 alkyl)-, wherein the nitrogen atom comprised in said -CO-NH- or said -CO- N(d- 4 alkyl)- is attached to ring A.
  • L is -CO-NH-, wherein the nitrogen atom comprised in said -CO-NH- is attached to ring A.
  • A is aryl or heteroaryl, wherein said aryl or said heteroaryl is optionally substituted with one or more groups (such as, e.g., one, two, three or four groups; preferably, one or two groups; more preferably, one group) independently selected from d prison 4 alkyl, C 2-4 alkenyl, C 2 . 4 alkynyl, -OH, -0(C 1-4 alkyl), -SH, -S(d. 4 alkyl), -NH 2 , -NH(d. 4 alkyl), -N(d. 4 alkyl)(C 1-4 alkyl), halogen, -CF 3 , or -CN.
  • groups such as, e.g., one, two, three or four groups; preferably, one or two groups; more preferably, one group
  • groups such as, e.g., one, two, three or four groups; preferably, one or two groups; more preferably, one group
  • groups such as, e
  • Said aryl is preferably phenyl or naphthyl, and more preferably said aryl is phenyl.
  • Said heteroaryl is preferably a heteroaryl having 5 or 6 ring atoms, wherein 1 , 2 or 3 of said ring atoms are heteroatoms independently selected from oxygen, sulfur or nitrogen, and the remaining ones of said ring atoms are carbon atoms, and further wherein said heteroaryl having 5 or 6 ring atoms is optionally fused to a benzene ring.
  • said heteroaryl is selected from thiazolyl (e.g., 1 ,3-thiazol-2-yl), furanyl, thiophenyl (i.e., thienyl), pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, furazanyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzothiazolyl (e.g., 1 ,3-benzothiazol-2-yl), benzofuranyl, benzothiophenyl, benzopyrrolyl, benzoimidazolyl, benzopyrazolyl, benzoxazolyl, benzisoxazolyl, benzofurazanyl, benzopyridinyl, benzopyrimidinyl, benzopyrazinyl, or benzopyridazinyl.
  • thiazolyl e.g
  • said heteroaryl is thiazolyl (e.g. , 1 ,3-thiazol-2-yl) or benzothiazolyl (e.g. , 1 ,3-benzothiazol-2-yl).
  • said heteroaryl is benzothiazolyl, particularly 1 .3-benzothiazol-2-yl.
  • A is aryl or heteroaryl, including any of the aforementioned preferred aryl or heteroaryl groups, wherein said aryl or heteroaryl is unsubstituted (i.e., is not substituted with any groups other than R 4 ).
  • A is phenyl, 1 ,3-thiazol-2-yl or 1 ,3-benzothiazol-2-yl, wherein said phenyl, said 1 ,3-thiazol-2-yl or said 1 ,3-benzothiazol-2-yl is optionally substituted with one or more (e.g., one, two or three) groups independently selected from C 1-4 alkyl, C 2 , 4 alkenyl, C 2 diligent 4 alkynyl, -OH, -0(d. 4 alkyl), -SH, -S(C 1-4 alkyl), -NH 2 , -NH(d_ 4 alkyl), -N(C 1-4 alkyl)(d.
  • A is phenyl, 1 ,3-thiazo!-2-yl or 1 ,3-benzothiazol-2-yl, wherein said phenyl, said 1 ,3-thiazol-2-yl or said 1 ,3-benzothiazol-2-yl is unsubstituted (i.e., is not substituted with any groups other than R 4 ). More preferably, A is phenyl which is optionally substituted with one or more (e.g., one, two or three) groups independently selected from d cycle alkyl, C 2-4 alkenyl, C 2 .
  • R 4 is selected from -CO-(C 1-4 alkyl), -CHO, -0(d. 4 alkyl), -OH, -0-CO-(C 1-4 alkyl), -0-CO-0(C 1-4 alkyl), -CO-0(d_ 4 alkyl), -COOH, -CO-NH 2 , -CO-NH-(C 1-4 alkyl), -CO-N(C 1-4 alkyl)(d. 4 alkyl), -0-CO-NH 2 , -0-CO-NH-(C 1-4 alkyl), -0-CO-N(d_ 4 alkyl)(d_ 4 alkyl), -NH-CO-(d.
  • R 4 is selected from -CO-(d. 4 alkyl), -CHO, -0(C 1-4 alkyl), -OH, -0-CO-(C 1-4 alkyl), -0-CO-0(C 1-4 alkyl), -CO-0(C 1-4 alkyl), -COOH, -CO-NH 2 , -CO-NH-(C 1-4 alkyl), -CO-N(C 1-4 alkyl)(C 1-4 alkyl), -0-CO-NH 2 , -0-CO-NH-(C 1-4 alkyl), -0-CO-N(C 1-4 alkyl)(C 1-4 alkyl), -NH-CO-(C 1-4 alkyl), -N(d.
  • R 4 alkyl), -CHO, -0(C 1-4 alkyl), or -OH. Even more preferably, R 4 is -CO-CH 3 , -CO-CH 2 CH 3 , -OCH 3 , or -OCH 2 CH 3 .
  • is a double bond. Accordingly, it is preferred that the compound of formula (I) has the following structure:
  • Particularly preferred compounds of formula (I) are the compounds 1a to 1t shown below as well as pharmaceutically acceptable salts, solvates and prodrugs of each one of these compounds:
  • PLCe141 (also referred to as “PKCe141 ”)
  • PLCe16 PLCe16
  • PLCe129 PLC 15
  • PLCe133 PLCe133
  • PLCe140 PLCe140
  • PLCe2140 PLC 15
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) as described and defined herein, or a pharmaceutically acceptable salt, solvate or prodrug thereof, in combination with a pharmaceutically acceptable excipient.
  • the compounds according to the present invention have been found to inhibit the interaction of PKCe with its adaptor protein RACK2, as also shown in Examples 2 and 3.
  • Compound 1 b which is an exemplary compound of formula (I) has been demonstrated to inhibit the PKCe/RACK2 interaction in vitro with an IC 50 of 5.9 ⁇ (see Example 2) and to inhibit the phosphorylation of the PKCe-downstream target Elk-1 in HeLa cells with an IC 50 of 1 1.2 ⁇ (see Example 3).
  • a large number of further exemplary compounds of formula (I) has likewise been found to inhibit PKCe signaling (see Example 2).
  • Compound 1 a for example, has been shown to inhibit the PKCe/RACK2 interaction in vitro with an IC 50 of 4.1 ⁇ .
  • the compounds of the present invention are particularly advantageous as they allow the isozyme-specific inhibition of PKCe signaling. Accordingly, it has been demonstrated in Example 4 that compound 1 b inhibits the TPA-induced translocation of PKCE - but not that of PKC5 - from the cytosol to the membrane and, furthermore, compound 1 b has been shown to inhibit the PKCe-induced migration of HeLa cells into a gap (see Example 5).
  • the compounds of the present invention thus fulfill all criteria of an inhibitor of PKCe signal transduction, such as inhibition of Elk-1 phosphorylation, inhibition of PKCe translocation to the membrane and inhibition of cell migration.
  • the compounds of the invention have been shown not to inhibit cell proliferation (see Example 5), which indicates a lack of toxicity and confirms the suitability of these compounds as medicaments.
  • the compounds according to the invention, and in particular the compounds of formula (I) can thus be used for the therapeutic intervention in diseases/disorders in which PKCe signaling is implicated (particularly diseases/disorders associated with an increased activity or a hyperactivity of PKCe signaling), such as, e.g., cardiovascular disorders (e.g., cardiac hypertrophy, hypertrophic cardiomyopathy, or heart failure (including, e.g., congestive heart failure)), anxiety, pain (e.g., chronic pain), migraine, allergies, inflammatory disorders, autoimmune disorders, diabetes (including also insulin resistance), diabetic complications (such as, e.g., diabetic retinopathy, diabetic nephropathy, diabetic cardiomyopathy, or diabetic neuropathy), cancer (such as, e.g., stomach cancer, lung cancer, thyroid cancer, colon cancer, breast cancer; including
  • the present invention provides a compound of formula (I) as described and defined herein, or a pharmaceutically acceptable salt, solvate or prodrug thereof, or a pharmaceutical composition comprising any of the aforementioned entities and a pharmaceutically acceptable excipient, for use in the treatment or prevention of cardiovascular disorders (e.g., cardiac hypertrophy, hypertrophic cardiomyopathy, or heart failure (including, e.g., congestive heart failure)), anxiety, pain (e.g., chronic pain), migraine, allergies, inflammatory disorders, autoimmune disorders, diabetes (including also insulin resistance), diabetic complications (such as, e.g.
  • cardiovascular disorders e.g., cardiac hypertrophy, hypertrophic cardiomyopathy, or heart failure (including, e.g., congestive heart failure)
  • anxiety e.g., chronic pain
  • migraine e.g., allergies, inflammatory disorders, autoimmune disorders, diabetes (including also insulin resistance), diabetic complications (such as, e.g.
  • diabetic retinopathy diabetic nephropathy
  • diabetic cardiomyopathy or diabetic neuropathy
  • cancer such as, e.g., stomach cancer, lung cancer, thyroid cancer, colon cancer, breast cancer; including also metastatic cancer, metastasis, drug-resistant cancer, or multidrug-resistant cancer
  • neurological disorders e.g., Alzheimer's disease, Parkinson's disease, bipolar disorder, or stroke; including also neurodegenerative disorders
  • alopecia e.g., Alzheimer's disease, Parkinson's disease, bipolar disorder, or stroke; including also neurodegenerative disorders
  • the invention likewise relates to the use of the compounds provided herein, including the compounds of formula (I) or pharmaceutically acceptable salts, solvates or prodrugs thereof, in the preparation of a medicament for the treatment or prevention of cardiovascular disorders (e.g., cardiac hypertrophy, hypertrophic cardiomyopathy, or heart failure (including, e.g., congestive heart failure)), anxiety, pain (e.g., chronic pain), migraine, allergies, inflammatory disorders, autoimmune disorders, diabetes (including also insulin resistance), diabetic complications (such as, e.g., diabetic retinopathy, diabetic nephropathy, diabetic cardiomyopathy, or diabetic neuropathy), cancer (such as, e.g., stomach cancer, lung cancer, thyroid cancer, colon cancer, breast cancer; including also metastatic cancer, metastasis, drug-resistant cancer, or multidrug-resistant cancer), neurological disorders (e.g., Alzheimer's disease, Parkinson's disease, bipolar disorder, or stroke; including also neurodegenerative disorders), alopecia, or alcoholism
  • the invention also provides a method of treating or preventing a disorder or condition selected from the group consisting of cardiovascular disorders (e.g., cardiac hypertrophy, hypertrophic cardiomyopathy, or heart failure (including, e.g., congestive heart failure)), anxiety, pain (e.g., chronic pain), migraine, allergies, inflammatory disorders, autoimmune disorders, diabetes (including also insulin resistance), diabetic complications (such as, e.g., diabetic retinopathy, diabetic nephropathy, diabetic cardiomyopathy, or diabetic neuropathy), cancer (such as, e.g., stomach cancer, lung cancer, thyroid cancer, colon cancer, breast cancer; including also metastatic cancer, metastasis, drug-resistant cancer, or multidrug-resistant cancer), neurological disorders (e.g., Alzheimer's disease, Parkinson's disease, bipolar disorder, or stroke; including also neurodegenerative disorders), alopecia, and alcoholism, the method comprising the administration of a compound according to the invention, particularly a compound of formula (I) or a pharmaceutical
  • Protein-protein interfaces such as the PKCe/RACK2 interface
  • PKCe/RACK2 interface Protein-protein interfaces, such as the PKCe/RACK2 interface
  • Iigand-binding sites due to their particular physicochemical properties (extensive, hydrophobic, surface-exposed interfaces).
  • Attempts to tackle protein-protein interactions have been reported in recent years but experience is still quite limited and experimental aspects are challenging as well (Rechfeid et al., 201 1 ).
  • the EAVSLKPT peptide derived from the binding site of PKCe to RACK2 and used for molecular modeling in the context of the present invention (see Example 1 ), inhibits this interaction with an IC 5C of 1 .02 ⁇ .
  • a peptidomimetic of EAVSLKPT such as compound 1 b (PKCe141 ) with an IC 50 of 5.9 ⁇ may be close to the optimum already.
  • aurothiomalate which prevents the interaction of PKCi and its adaptor protein Par6, is active in the range of 10 ⁇ (Erdogan et al., 2006). While a compound with an IC 50 in the nanomolar range would be preferable, this is not essential for clinical application.
  • the ribonucleotide reductase inhibitor hydroxyurea inhibits ribonucleotide reductase with an IC 50 of 37.2 ⁇ (Easmon et al., 2001 ) and is used in the clinic as an anticancer agent.
  • IC 50 37.2 ⁇
  • many clinically relevant kinase inhibitors which are active at nanomolar concentrations in vitro have cellular IC 50 values closer to the micromolar range due to the higher physiological concentrations of ATP relative to those typically used for in vitro assays.
  • the invention further relates to novel compounds, namely the compounds 1 a, 1j, 1 k, 11, 1 m, 1 n, 1 o, 1 p, 1 q, 1 r, 1s and 1t having the structures shown above, as well as pharmaceutically acceptable salts, solvates and prodrugs of each one of these compounds.
  • novel compounds namely the compounds 1 a, 1j, 1 k, 11, 1 m, 1 n, 1 o, 1 p, 1 q, 1 r, 1s and 1t having the structures shown above, as well as pharmaceutically acceptable salts, solvates and prodrugs of each one of these compounds.
  • These compounds as provided in the context of the present invention are particularly useful as medicaments, e.g., for the treatment or prevention of diseases/disorders in which PKCE signaling is implicated, as described herein above.
  • the present invention also relates to the compounds shown in Table 1 below, including in particular the compounds PKCe22, PKCe39, PKCe40, PKCe48, PKCe49, PKCe52, PKCe67, PKCe73, PKCe76, PKCe86, PKCe87, PKCe89, PKCe95, PKCe96, PKCe97, PKCe106, PKCe107, PKCe109, PKCe1 14, PKCe125, PKCe143, PKCe145, PKCe2019, PKCe2020, PKCe2021 , PKCe2051 , PKCe2052, PKCe2053, PKCe2054, PKCe2088, PKCe2089, PKCe2090, and PKCe2091 , as well as pharmaceutically acceptable salts, solvates and prodrugs of each one of these compounds.
  • the invention further relates to the use of these compounds as medicaments, including their use in the treatment or prevention of diseases/disorders in which PKCe signaling is implicated, such as the specific diseases/disorders described herein above.
  • the compounds of the present invention including the compounds of formula (I), can be prepared by methods known in the field of synthetic chemistry.
  • the compounds of the invention may be prepared in accordance with or in analogy to the synthetic routes described in Example 8.
  • alkyl refers to a monovalent saturated aliphatic (i.e. non-aromatic) acyclic hydrocarbon group (i.e., a group consisting of carbon atoms and hydrogen atoms), which may be linear or branched and does not comprise any carbon-to- carbon double bond or any carbon-to-carbon triple bond.
  • C 1-4 alkyl denotes an alkyl group having 1 to 4 carbon atoms.
  • Preferred exemplary alkyl groups are methyl, ethyl, propyl, or butyl.
  • alkenyl refers to a monovalent unsaturated aliphatic acyclic hydrocarbon group, which may be linear or branched and comprises at least one carbon-to- carbon double bond while it does not comprise any carbon-to-carbon triple bond.
  • C 2 -4 alkenyl denotes an alkenyl group having 2 to 4 carbon atoms.
  • Preferred exemplary alkenyl groups are ethenyl, propenyl, or butenyl.
  • alkynyl refers to a monovalent unsaturated aliphatic acyclic hydrocarbon group, which may be linear or branched and comprises at least one carbon-to- carbon triple bond and optionally one or more carbon-to-carbon double bonds.
  • C 2 -4 alkynyl denotes an alkynyl group having 2 to 4 carbon atoms.
  • Preferred exemplary alkynyl groups are ethynyl, propynyl, or butynyl.
  • aryl refers to a monovalent aromatic hydrocarbon group, including bridged ring and/or fused ring systems, containing at least one aromatic ring.
  • Aryl may, for example, refer to phenyl, naphthyl or anthracenyl.
  • heteroaryl refers to a monovalent aromatic ring group, which may be a monocyclic ring group or a bridged ring and/or fused ring system (e.g., a bicyclic ring system), said aromatic ring group comprising one or more (such as, e.g., one, two, or three) ring heteroatoms independently selected from O, S, or N, wherein the aromatic ring group may, e.g., have 5 to 14 (particularly 5 or 6) ring atoms.
  • heteroaryl groups include thiazolyl (e.g., 1 ,3-thiazol-2-yl), furanyl, thiophenyl (i.e., thienyl), pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, furazanyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzothiazolyl (e.g., 1 ,3-benzothiazol-2-yl), benzofuranyl, benzothiophenyl, benzopyrrolyl, benzoimidazolyl, benzopyrazolyl, benzoxazolyl, benzisoxazolyl, benzofurazanyl, benzopyridinyl, benzopyrimidinyl, benzopyrazinyl, or benzopyridazinyl.
  • thiazolyl e.g.,
  • heterocycloalkyi refers to a 3 to 10 atom ring or ring system containing one or more (e.g., one, two or three) ring heteroatoms independently selected from O, S, or N.
  • Heterocycloalkyi may, for example, refer to tetrahydrofuranyl, piperidinyl, piperazinyl, aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, morpholinyl (e.g., morpholin-4- yl), pyrazolidinyl, tetrahydrothienyl, octahydroquinolinyl, octahydroisoquinolinyl, oxazolidinyl, or isoxazolidinyl.
  • halogen refers to fluoro (-F), chloro (-CI), bromo (-Br) or iodo (-I).
  • the scope of the invention embraces all pharmaceutically acceptable salt forms of the compounds provided herein, including in particular the compounds of formula (I), which may be formed, e.g., by protonation of an atom carrying an electron lone pair which is susceptible to protonation, such as an amino group, with an inorganic or organic acid, or as a salt of a carboxylic acid group with a physiologically acceptable cation as they are well-known in the art.
  • Exemplary base addition salts comprise, for example, alkali metal salts such as sodium or potassium salts; alkaline earth metal salts such as calcium or magnesium salts; ammonium salts; aliphatic amine salts such as trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, procaine salts, meglumine salts, or ethylenediamine salts; aralkyl amine salts such as N,N- dibenzylethylenediamine salts, benethamine salts; heterocyclic aromatic amine salts such as pyridine salts, picoline salts, quinoline salts or isoquinoline salts; quaternary ammonium salts such as tetramethylammonium salts, tetraethylammonium salts, benzyltrimethylammonium salts, benzyltriethylammonium salts, benzyltributylammonium salts,
  • Exemplary acid addition salts comprise, for example, mineral acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate salts, nitrate salts, phosphate salts (such as, e.g., phosphate, hydrogenphosphate, or dihydrogenphosphate salts), carbonate salts, hydrogencarbonate salts or perchlorate salts; organic acid salts such as acetate, propionate, butyrate, pentanoate, hexanoate, heptanoate, octanoate, cyclopentanepropionate, undecanoate, lactate, maleate, oxalate, fumarate, tartrate, malate, citrate, nicotinate, benzoate, salicylate or ascorbate salts; sulfonate salts such as methanesulfonate, ethanesulfonate, 2-hydroxyethanesulfonate, benzenesulfonate
  • the scope of the invention embraces the compounds provided herein, including in particular the compounds of formula (I), in any solvated form, including, e.g., solvates with water, for example hydrates, or with organic solvents such as, e.g., methanol, ethanol or acetonitrile, i.e., as a methanolate, ethanolate or acetonitrilate, respectively, or in the form of any polymorph.
  • the formulae in the present specification are intended to cover all possible stereoisomers, including enantiomers and diastereomers, of the indicated compounds.
  • all stereoisomers of the compounds of the present invention are contemplated as part of the present invention, either in admixture or in pure or substantially pure form.
  • the scope of the compounds according to the invention embraces all of the possible stereoisomers and their mixtures, it particularly embraces the racemic forms and the isolated optical isomers.
  • the racemic forms can be resolved by physical methods, such as, e.g., fractional crystallization, separation or crystallization of diastereomeric derivatives or separation by chiral column chromatography.
  • the individual optical isomers can be obtained from the racemates using conventional methods, such as, e.g., salt formation with an optically active acid followed by crystallization.
  • the present invention also embraces all possible tautomers of the compounds provided herein, including the compounds of formula (I).
  • Pharmaceutically acceptable prodrugs of the compounds according to the present invention are derivatives which have chemically or metabolically cleavable groups and become, by solvolysis or under physiological conditions, the compounds of the invention which are pharmaceutically active in vivo.
  • Prodrugs of compounds according to the the present invention may be formed in a conventional manner with a functional group of the compounds such as, e.g., with an amino, hydroxy or carboxy group.
  • the prodrug derivative form often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see, Bundgaard, H., Design of Prodrugs, pp.
  • Prodrugs include acid derivatives well known to the person skilled in the art, such as, for example, esters prepared by reaction of the parent acidic compound with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a suitable amine.
  • esters prepared by reaction of the parent acidic compound with a suitable alcohol
  • amides prepared by reaction of the parent acid compound with a suitable amine.
  • a compound of the present invention has a carboxyl group
  • an ester derivative prepared by reacting the carboxyl group with a suitable alcohol or an amide derivative prepared by reacting the carboxyl group with a suitable amine is exemplified as a prodrug.
  • An especially preferred ester derivative as a prodrug is methylester, ethylester, n- propylester, isopropylester, n-butylester, isobutylester, tert-butylester, morpholinoethylester, ⁇ , ⁇ -diethyiglycolamidoester or a-acetoxyethylester.
  • a compound of the present invention has a hydroxy group
  • an acyloxy derivative prepared by reacting the hydroxyl group with a suitable acylhalide or a suitable acid anhydride is exemplified as a prodrug.
  • an amide derivative prepared by reacting the amino group with a suitable acid halide or a suitable mixed anhydride is exemplified as a prodrug.
  • the compounds described herein may be administered as compounds per se or may be formulated as medicaments.
  • the medicaments/pharmaceutical compositions may comprise one or more pharmaceutically acceptable excipients, such as carriers, diluents, fillers, disintegrants, lubricating agents, binders, colorants, pigments, stabilizers, preservatives, antioxidants, or solubility enhancers.
  • the pharmaceutical compositions may comprise one or more solubility enhancers, such as, e.g., poly(ethylene glycol), including poly(ethylene glycol) having a molecular weight in the range of about 200 to about 5,000 Da, ethylene glycol, propylene glycol, non-ionic surfactants, tyloxapol, polysorbate 80, macrogol-15-hydroxystearate, phospholipids, lecithin, dimyristoyl phosphatidylcholine, dipalmitoyl phosphatidylcholine, distearoyl phosphatidylcholine, cyclodextrins, hydroxyethyl-p-cyclodextrin, hydroxypropyl- ⁇ - cyclodextrin, hydroxyethyl-y-cyclodextrin, hydroxypropyl-v-cyclodextrin, dihydroxypropyl- ⁇ - cyclodextrin, glucosyl-a-cyclodextrin,
  • the pharmaceutical compositions can be formulated by techniques known to the person skilled in the art, such as the techniques published in Remington's Pharmaceutical Sciences, 20 th Edition.
  • the pharmaceutical compositions can be formulated as dosage forms for oral, parenteral, such as intramuscular, intravenous, subcutaneous, intradermal, intraarterial, intracardial, rectal, nasal, topical, aerosol or vaginal administration.
  • Dosage forms for oral administration include coated and uncoated tablets, soft gelatin capsules, hard gelatin capsules, lozenges, troches, solutions, emulsions, suspensions, syrups, elixirs, powders and granules for reconstitution, dispersible powders and granules, medicated gums, chewing tablets and effervescent tablets.
  • Dosage forms for parenteral administration include solutions, emulsions, suspensions, dispersions and powders and granules for reconstitution. Emulsions are a preferred dosage form for parenteral administration.
  • Dosage forms for rectal and vaginal administration include suppositories and ovula.
  • Dosage forms for nasal administration can be administered via inhalation and insufflation, for example by a metered inhaler.
  • Dosage forms for topical administration include creams, gels, ointments, salves, patches and transdermal delivery systems.
  • the compounds according to the invention in particular the compounds of formula (I), or the above described pharmaceutical compositions comprising one or more compounds of formula (I) may be administered to a subject by any convenient route of administration, whether systemically/peripherally or at the site of desired action, including but not limited to one or more of: oral (e.g., as a tablet, capsule, or as an ingestible solution), topical (e.g., transdermal, intranasal, ocular, buccal, and sublingual), parenteral (e.g., using injection techniques or infusion techniques, and including, for example, by injection, e.g., subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, or intrasternal by, e.g., implant of a depot, for example, subcutaneously or
  • examples of such administration include one or more of: intravenously, intraarterially, intraperitoneal ⁇ , intrathecally, intraventricular ⁇ , intraurethrally, intrasternally, intracardially, intracranially, intramuscularly or subcutaneously administering the compounds or pharmaceutical compositions, and/or by using infusion techniques.
  • parenteral administration the compounds are best used in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood.
  • the aqueous solutions should be suitably buffered (preferably to a pH of from 3 to 9), if necessary.
  • the preparation of suitable parenteral formulations under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.
  • Said compounds or pharmaceutical compositions can also be administered orally in the form of tablets, capsules, ovules, elixirs, solutions or suspensions, which may contain flavoring or coloring agents, for immediate-, delayed-, modified-, sustained-, pulsed- or controlled-release applications.
  • the tablets may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate and glycine, disintegrants such as starch (preferably corn, potato or tapioca starch), sodium starch glycolate, croscarmellose sodium and certain complex silicates, and granulation binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, stearic acid, glyceryl behenate and talc may be included. Solid compositions of a similar type may also be employed as fillers in gelatin capsules.
  • excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate and glycine
  • disintegrants such as starch (preferably corn, potato or tapioca starch), sodium starch glyco
  • Preferred excipients in this regard include lactose, starch, a cellulose, or high molecular weight polyethylene glycols.
  • the agent may be combined with various sweetening or flavoring agents, coloring matter or dyes, with emulsifying and/or suspending agents and with diluents such as water, ethanol, propylene glycol and glycerin, and combinations thereof.
  • said compounds or pharmaceutical compositions can be administered in the form of a suppository or pessary, or it may be applied topically In the form of a gel, hydrogel, lotion, solution, cream, ointment or dusting powder.
  • the compounds of the present invention may also be dermally or transdermally administered, for example, by the use of a skin patch.
  • sustained-release compositions include semi-permeable polymer matrices in the form of shaped articles, e.g., films, or microcapsules.
  • Sustained-release matrices include, e.g., polylactides (U.S. Pat. No. 3,773,919), copolymers of L-glutamic acid and gamma-ethyl-L-glutamate (Sidman, U. et al., Biopolymers 22:547-556 (1983)), poly(2-hydroxyethyl methacrylate) (R. Langer et al., J. Biomed. Mater. Res.
  • Sustained-release pharmaceutical compositions also include liposomally entrapped compounds.
  • Liposomes containing a compound of the present invention can be prepared by methods known in the art, such as, e.g., the methods described in any one of: DE3218121 ; Epstein et al., Proc. Natl. Acad. Sci. (USA) 82:3688-3692 (1985); Hwang et al., Proc. Natl. Acad. Sci.
  • Said compounds or pharmaceutical compositions may also be administered by the pulmonary route, rectal routes, or the ocular route.
  • they can be formulated as micronized suspensions in isotonic, pH adjusted, sterile saline, or, preferably, as solutions in isotonic, pH adjusted, sterile saline, optionally in combination with a preservative such as a benzalkonium chloride.
  • they may be formulated in an ointment such as petrolatum.
  • dry powder formulations of the compounds of the present invention including the compounds of formula (I), for pulmonary administration, particularly inhalation.
  • Such dry powders may be prepared by spray drying under conditions which result in a substantially amorphous glassy or a substantially crystalline bioactive powder.
  • dry powders of the compounds of the present invention can be made according to the emulsification/spray drying process disclosed in WO 99/16419 or WO 01/85136. Spray drying of solution formulations of the compounds of the present invention is carried out, for example, as described generally in the "Spray Drying Handbook", 5th ed., K. Masters, John Wiley & Sons, Inc. , NY, NY (1991 ), and in WO 97/41833 or WO 03/05341 1 .
  • said compounds or pharmaceutical compositions can be formulated as a suitable ointment containing the active compound suspended or dissolved in, for example, a mixture with one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, emulsifying wax and water.
  • they can be formulated as a suitable lotion or cream, suspended or dissolved in, for example, a mixture of one or more of the following: mineral oil, sorbitan monostearate, a polyethylene glycol, liquid paraffin, polysorbate 60, cetyl esters wax, 2-octyldodecanol, benzyl alcohol and water.
  • a proposed, yet non-limiting dose of the compounds according to the invention, particularly the compounds of formula (I), for oral administration to a human may be 0.05 to 2500 mg, preferably 0.1 mg to 1000 mg, of the active ingredient per unit dose.
  • the unit dose may be administered, for example, 1 to 3 times per day.
  • the unit dose may also be administered 1 to 7 times per week, e.g., with not more than one administration per day. It will be appreciated that it may be necessary to make routine variations to the dosage depending on the age and weight of the patient/subject as well as the severity of the condition to be treated. The precise dose and also the route of administration will ultimately be at the discretion of the attendant physician or veterinarian.
  • the subject or patient may be an animal (e.g., a non-human animal), a vertebrate animal, a mammal, a rodent (e.g., a guinea pig, a hamster, a rat, a mouse), a murine (e.g., a mouse), a canine (e.g., a dog), a feline (e.g., a cat), a porcine (e.g., a pig), an equine (e.g., a horse), a primate, a simian (e.g., a monkey or ape), a monkey (e.g., a marmoset, a baboon), an ape (e.g., a gorilla, chimpanzee, orang-utan, gibbon), or a human.
  • an animal e.g., a non-human animal
  • a vertebrate animal e.g.,
  • Non-limiting examples of agronomically important animals are sheep, cattle and pigs, while, for example, cats and dogs may be considered as economically important animals.
  • the subject/patient is a mammal; more preferably, the subject/patient is a human or a non-human mammal (such as, e.g., a guinea pig, a hamster, a rat, a mouse, a rabbit, a dog, a cat, a horse, a monkey, an ape, a marmoset, a baboon, a gorilla, a chimpanzee, an orang-utan, a gibbon, a sheep, cattle, or a pig); even more preferably, the subject/patient is a human.
  • a non-human mammal such as, e.g., a guinea pig, a hamster, a rat, a mouse, a rabbit, a dog, a cat, a horse
  • Treatment of a disorder or disease is well known in the art.
  • Treatment of a disorder or disease implies that a disorder or disease is suspected or has been diagnosed in a patient/subject.
  • a patient/subject suspected of suffering from a disorder or disease typically shows specific clinical and/or pathological symptoms which a skilled person can easily attribute to a specific pathological condition (i.e., diagnose a disorder or disease).
  • Treatment of a disorder or disease may, for example, lead to a halt in the progression of the disorder or disease (e.g., no deterioration of symptoms) or a delay in the progression of the disorder or disease (in case the halt in progression is of a transient nature only).
  • Treatment of a disorder or disease may also lead to a partial response (e.g., amelioration of symptoms) or complete response (e.g., disappearance of symptoms) of the subject/patient suffering from the disorder or disease.
  • “Amelioration” of a disorder or disease may, for example, lead to a halt in the progression of the disorder or disease or a delay in the progression of the disorder or disease. Such a partial or complete response may be followed by a relapse. It is to be understood that a subject/patient may experience a broad range of responses to a treatment (e.g., the exemplary responses as described herein above).
  • Treatment of a disorder or disease may, inter alia, comprise curative treatment (preferably leading to a complete response and eventually to healing of the disorder or disease) and palliative treatment (including symptomatic relief).
  • a patient/subject suspected of being prone to suffer from a disorder or disease as defined herein may, in particular, benefit from a prevention of the disorder or disease.
  • the subject/patient may have a susceptibility or predisposition for a disorder or disease, including but not limited to hereditary predisposition.
  • Such a predisposition can be determined by standard assays, using, for example, genetic markers or phenotypic indicators. It is to be understood that a disorder or disease to be prevented in accordance with the present invention has not been diagnosed or cannot be diagnosed in the patient/subject (for example, the patient/subject does not show any clinical or pathological symptoms).
  • prevention comprises the use of compounds of the present invention before any clinical and/or pathological symptoms are diagnosed or determined or can be diagnosed or determined by the attending physician.
  • a number of documents including patent applications, scientific literature and manufacturers' manuals are cited. The disclosure of these documents, while not considered relevant for the patentability of this invention, is herewith incorporated by reference in its entirety. More specifically, all referenced documents are incorporated by reference to the same extent as if each individual document was specifically and individually indicated to be incorporated by reference. The present invention particularly relates to the following items: 1.
  • n is an integer of 0 to 4, and each R 1 is independently selected from C 2 . 4 alkyl, C 2 . 4 alkenyl, C 2 . 4 alkynyl, -OH, -0(d. 4 alkyl), -0(d. 4 alkyl)-OH, -0(C 1-4 alkyl)-0(C 1-4 alkyl), -SH, -S(C 1-4 alkyl), -S(C V4 alkyl)-SH, or -S(d. 4 alkyl)-S(C 1-4 alkyl), -NH 2 , -NH(C 1-4 alkyl), -N(C,. 4 alkyl)(C 1-4 alkyl), halogen, -CF 3 , or -CN;
  • n 2, 3 or 4
  • two groups R 1 attached to adjacent carbon atoms are mutually linked to form a group -0-CH 2 -0-, -0-CH 2 -CH 2 -0- or -0-CH 2 -CH 2 -CH 2 -0-, while the further group(s) R 1 , if present, is/are independently selected from C 1 .4 alkyl, C 2 . 4 alkenyl, C 2 . 4 alkynyl, -OH, -0(C -4 alkyl), -0(d_ 4 alkyl)-OH, -0(d. 4 alkyl)-0(d.
  • R 2 is selected from hydrogen, C 1-4 alkyl, C 2 . 4 alkenyl, C 2 . 4 alkynyl, -OH, -0(d. 4 alkyl), -SH, -S(d. 4 alkyl), -NH 2 , -NH(d. 4 alkyl), -N(d. 4 alkyl)(d. 4 alkyl), halogen, -CF 3 , or -CN;
  • R 3 is selected from -NH 2 , -NH(d. 4 alkyl), -N(C 1-4 alkyl)(C 1-4 alkyl), -OH, -0(Ci. 4 alkyl), -SH, -S(d_ 4 alkyl), or hydrogen;
  • X is selected from S, O, N(H), or N(dminister 4 alkyl);
  • L is -(CH 2 )i-4-, wherein one -CH 2 - unit comprised in said -(CH 2 )i-4- is replaced by a group selected from -CO-NH-, -CO-N(d).
  • A is aryl or heteroaryl, wherein said aryl or said heteroaryl is optionally substituted with one or more groups independently selected from d- 4 alkyl, C 2 .4 alkenyl, C 2 . 4 alkynyl, -OH, -0(C 1-4 alkyl), -SH, -S(C 1-4 alkyl), -NH 2 , -NH(C 1-4 alkyl), -N(d.
  • R 4 is selected from -CO-(C 1-4 alkyl), -CHO, -0(d- 4 alkyl), -OH, -0-CO-(C 1-4 alkyl), -0-CO-0(C 1-4 alkyl), -CO-0(d. 4 alkyl), -COOH, -CO-NH 2 , -CO-NH-(d. 4 alkyl), -CO-N(d_ 4 alkyl)(d- 4 alkyl), -0-CO-NH 2 , -0-CO-NH-(d.
  • n is an integer of 1 to 4, one group R 1 is selected from -0(d. 4 alkyl), -OH, -0(C 1-4 alkyl)-OH, or -0(C 1-4 alkyl)-0(C 1-4 alkyl), and the remaining group(s) R 1 , if present, is/are independently selected from C 2 - 4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, -OH, -0(C 1-4 alkyl), -0(C 1-4 alkyl)-OH, -0(C 1-4 alkyl)-0(C 1 . 4 alkyl), -SH, -S(d.
  • n 2, 3 or 4
  • two groups R 1 attached to adjacent carbon atoms are mutually linked to form a group -0-CH 2 -0-, -0-CH 2 -CH 2 -0- or -0-CH 2 -CH 2 -CH 2 -0-
  • the further group(s) R 1 if present, is/are independently selected from C 1-4 alkyl, C 2 _ 4 alkenyl, C 2-4 alkynyl, -OH, -0(C 1-4 alkyl), -0(d_ 4 alkyl)-OH, -0(d.
  • A is phenyl, 1 ,3-thiazol-2-yl or 1 ,3-benzothiazol-2-yl, wherein said phenyl, said 1 ,3-thiazol-2-yl or said 1 ,3-benzothiazol-2-yl is optionally substituted with one or more groups independently selected from C -4 alkyl, C 2 _ 4 alkenyl, C 2 _ 4 alkynyl, -OH, -0(d. alkyl), -SH, -S(d_ 4 alkyl), -NH 2 , -NH(C 1-4 alkyl), -N(C,. 4 alkyl)(d.
  • R 4 is selected from -CO-(Ci_4 alkyl), -CHO, -0(C 1-4 alkyl), -OH, -CO-0(C 1-4 alkyl), -COOH, C 1-4 alkyl, -(C 1-4 alkyl)-CO-(d.
  • a pharmaceutical composition comprising a compound as defined in any of Items 1 to 10 or a pharmaceutically acceptable salt, solvate or prodrug thereof, and a pharmaceutically acceptable excipient, for use in the treatment or prevention of a cardiovascular disorder, cardiac hypertrophy, heart failure, anxiety, pain, chronic pain, migraine, an allergy, an inflammatory disorder, an autoimmune disorder, diabetes, diabetic complications, diabetic retinopathy, diabetic nephropathy, diabetic cardiomyopathy, diabetic neuropathy, cancer, metastatic cancer, drug-resistant cancer, stomach cancer, lung cancer, thyroid cancer, colon cancer, breast cancer, bipolar disorder, stroke, alopecia, or alcoholism.
  • a pharmaceutical composition comprising a compound as defined in item 16 or a pharmaceutically acceptable salt, solvate or prodrug thereof, and a pharmaceutically acceptable excipient.
  • FIG. 1 Structure-based modeling of the mimic of the PKCe protein fragment EAVSLKPT (see Example 1 ).
  • A X-ray structure of PKCe (PDB 1 gmi). The protein backbone is illustrated as cartoon, while the EAVSLKPT is highlighted as sticks in a light grey box.
  • B Extracted protein fragment EAVSLKPT in its conformation observed in the X-ray structure. Hydrogen bond donor and acceptor features (dark grey spheres) as well as the hydrophobic interaction area (light grey sphere) are indicated for the pharmacophore model that retrieved compound 1 c (PKCe16) as a hit.
  • FIG. 2 Effects of compounds 1 a (PKCe2138) and 1 b (PKCe141 ) in vitro and in vivo (see Examples 2 and 3).
  • Compound 1 b (referred to as “compound 141 ") prevents the in vitro interaction of ⁇ with RACK2 in a dose-dependent manner.
  • Compound 1 b (PKCe141 ) inhibits the phosphorylation of Elk-1 in PathDetect HeLa HLR cells. Luciferase activity following activation of Elk-1 is shown. Data shown are the means (+/-SD) of 3 independent experiments.
  • C Compound 1 b (PKCe141 ) does not prevent the in vitro interaction between ⁇ and RACK1 .
  • E Compound 1 a (PKCe2138) prevents RACK2-binding to PKCs in vitro in a dose-dependent manner.
  • F Inhibition of RACK2-binding to PKC in vitro by EAVSLKPT which was tagged with seven arginines. A scrambled octapeptide tagged with seven arginines was used as control.
  • FIG. 3 PKCe induces phosphorylation of Elk-1 .
  • A In HeLa cells, a doxycycline-inducible constitutively active PKCe (Xuan et al., 2005) leads to phosphorylation of Elk-1 . The cells were left untreated or induced with doxycycline (2 pg/ml) for 24 hours. Additional stimulation with TPA (50 nM) was performed for 10 minutes. Phosphorylation of Elk-1 was detected with a phospho-specific antibody against the Ser383 residue of Elk-1 . GAPDH was used as loading control.
  • B Densitometric analysis of Western blots.
  • FIG. 4 Effect of compound 1 b (PKCe141 ) on PKCe and PKC5 translocation (see Example 4).
  • IGF!- R and GAPDH were used as loading controls for the membrane and the cytosolic fraction, respectively.
  • the means of three independent experiments were scanned and shown in a graph (+/-SD).
  • FIG. 5 Effect of compound 1 b (PKCe141 ) on PKC isozymes. 50 ⁇ compound 1 b were used in a PKC assay as described in Examples 4 and 6.
  • FIG. 6 Cell proliferation following treatment with compound 1 b (PKCe141 ). Cell proliferation was determined as described in Example 5. The means (+/-SD) of three independent experiments, in which three samples were taken within each experiment, are shown.
  • Figure 7 Effect of compound 1 b (PKCe141 ) on PKCe translocation by immunofluorescence. PC-3 cells were employed for these experiments. TPA induces translocation of PKCe to the plasma membrane. Compound 1 b inhibits this TPA-induced translocation of PKCe. Experiments 1 , 2 and 3 are three independent experiments.
  • FIG 8 PKCe-induced migration of HeLa cells into a gap. The expression of constitutively active PKCe was induced by doxycycline for 24 hours after a scratch was made into monolayer cells with a pipette tip.
  • Figure 9 Inhibition of angiogenesis in vitro (see Example 7).
  • Figure 10 1 H-NMR spectrum (A) and mass spectrum (B) of compound 1a (PKCe2138).
  • a pharmacophore model was derived from the PKCe protein fragment EAVSLKPT using its conformation observed in the crystal structure of PDB entry 1 gmi (Figs. 1A and 1 B). Catalyst (version 4.1 1 , Accelrys inc., San Diego, CA, USA) was employed for pharmacophore modeling and subsequent screening of commercial molecular libraries.
  • the pharmacophore model consists of three hydrogen bond donor/acceptor features and one hydrophobic feature. The latter attempts to resemble the hydrophobic area presented to RACK2 by Val16, while the hydrogen bond donor/acceptor features characterize the side chain properties of Ser17, Lys19, and Glu14.
  • PKCe141 (N-(3-acetylphenyl)- 9-amino-2,3-dihydro-1 ,4-dioxino[2,3-g]thieno[2,3-b]quinoline-8-carboxamide; Asinex ID: ASN 05545158; CAS 602293-00-5) was identified as the strongest disruptor/inhibitor of the PKCe/RACK2 interaction.
  • This screening process was followed by custom synthesis and testing of a series of further compounds related to compound 1 b (PKCe2019 to PKCe2145).
  • PKCe/RACK2 in vitro binding assay Recombinant RACK2 tagged with maltose-binding protein (RACK2-MBP) was purified on columns with amylose resin (New England Biolabs) as described by the manufacturer. The recombinant protein was analyzed by Coomassie Blue staining and Western blotting after SDS-PAGE. Aliquots were stored in liquid nitrogen. The interaction between PKCe and RACK2 was measured using an ELISA-based assay.
  • 96-well EIA/RIA high binding plates (Costar) were coated with 100 ng recombinant PKCe (ProQinase) in buffer A (20 mM Tris-HCI/100 m NaCI, pH 7.5) at 4°C on a shaker with gentle agitation overnight. The plate was washed twice with 225 ⁇ l/well buffer A. After blocking of unspecific binding sites with 225 ⁇ sterile-filtered 3 % bovine serum albumin (BSA; Sigma) in buffer A at room temperature for 3 h, the plate was washed twice with 225 ⁇ of this buffer.
  • PKCe ProQinase
  • buffer A 20 mM Tris-HCI/100 m NaCI, pH 7.5
  • BSA bovine serum albumin
  • PKCe was left untreated or activated by addition of 60 pg/ml phosphatidylserine (Sigma) and 100 nM TPA (Sigma) in a volume of 50 ⁇ buffer A for 10 min at 30°C.
  • Recombinant purified RACK2-MBP was either left untreated or incubated with EAVSLKPT-R7 or compound 1 b (PKCe141 ) at room temperature for 30 min in a final volume of 50 ⁇ buffer A.
  • 500 ng RACK2-MBP was added to untreated or activated PKCe for 1 hour at room temperature for binding. The plate was washed twice with 225 ⁇ buffer A.
  • 100 ⁇ RACK2-specific rabbit anti-RACK2 polyclonal antibody (Prof. F.
  • PKCpil/RACK1 in vitro binding assay This assay was similar to the PKCE/RACK2 binding assay described above. 6-his-tagged RACK1 was cloned into a pET-30a(+) vector (Novagen) and purified with Ni-NTA Agarose (Qiagen). Final elution was performed with 500 nM imidazole in elution buffer (20 mM Tris-HCI/300 mM NaCI, 20% glycerol, pH 7.5). The integrity of purified recombinant protein was analyzed by Coomassie Blue staining and Western blotting.
  • RACK1 200 ng RACK1 was coated onto 96-well EIA/RIA high binding plates (Costar) at 4°C on a shaker with gentle agitation overnight.
  • Compound 1 b (PKCe141 ) was added at room temperature for 30 min.
  • the RACK1 - coated plates with and without compound 1 b were incubated for 1 h with activated ⁇ .
  • the peptide EAVSLKPT-RRRRRRR was used as a control. Seven arginines were added to EAVSLKPT to increase internalization of the peptide into intact cells in in vivo experiments. ICso for the inhibition of the PKCe/RACK2 interaction by EAVSLKPT-RRRRRRR in this assay was 1.02 ⁇ (Fig. 2F). It has been shown previously that ⁇ interacts with the adaptor protein RACK1 (Ron et al., 1999). Therefore, it was investigated whether compound 1 b can also prevent the PKCpil/RACK1 interaction. As shown in Fig. 2C, compound 1 b does not prevent the PKCpil/RACK1 interaction, indicating specificity of this compound for the PKCe/RACK2 interaction.
  • compounds of formula (I) such as, e.g., compounds 1 a and 1 b, selectively inhibit PKCe signaling by preventing the interaction between PKCe and its adaptor protein RACK2.
  • the compounds of the invention are therefore suitable as therapeutic agents for the treatment or prevention of diseases/disorders related to PKCe signaling, as also described herein above.
  • Table 1 Inhibition of PKCe signaling.
  • the inhibition of the PKCE/RACK2 interaction is expressed as a percentage of untreated control. Accordingly, a value of, e.g., 37.7% denotes an inhibition of the PKCE/RACK2 interaction to 37.7% of the untreated control (which is set to 100%).
  • Compounds having a percentage inhibition of 100% or greater were not found to inhibit PKCe signaling in this assay.
  • PKCE is situated in the signal transduction cascade upstream of Raf-1 (Xuan et al., 2005).
  • active PKCE leads to phosphorylation of the transcription factor Elk-1 (see Fig. 3).
  • compound 1 b PLCe141
  • HLR PathDetect HeLa Luciferase
  • HeLa HLR and PC-3 cells were seeded at -10,000 cells per well in 96-well plates. After 4 h various concentrations of compound 1 b (PKCe141 ) were added and left for 72 h. Cell proliferation was determined by the SRB-assay (Skehan et al., 1990). Elk-1 phosphorylation: Elk-1 phosphorylation was determined with the PathDetect System (Agilent). PathDetect HeLa HLR-ELK-1 cells contain a luciferase reporter cassette and express a unique, stably integrated, irans-acting fusion protein.
  • the fusion protein consists of the activation domain of the Elk-1 transcriptional activator (Rao et al., 1989; Price et al., 1995; Marais et al. , 1993), that is fused to the yeast GAL4 DBD (residues 1-147).
  • the transcriptional activator domain of Elk-1 is activated.
  • 200,000 PathDetect HeLa HLR-Elk-1 cells per well were seeded in a 6-well plate and grown for 24 hours. Cells were washed with phosphate buffered saline and starved for 16 hours in starvation medium (DMEM-containing 0.5% fetal bovine serum and 1 % glutamine). Compounds were added in DMEM for 30 min.
  • the membranes were incubated with rabbit polyclonal IgG antibodies for detection of PKCe (Santa Cruz Biotechnology, dilution 1 :2,000), of PKCe phosphoSer 729 (Millipore, dilution 1 :1 ,000) and of PKC5 (Santa Cruz; dilution 1 :1 ,000).
  • rabbit polyclonal IgG antibodies for detection of PKCe (Santa Cruz Biotechnology, dilution 1 :2,000), of PKCe phosphoSer 729 (Millipore, dilution 1 :1 ,000) and of PKC5 (Santa Cruz; dilution 1 :1 ,000).
  • an IGFI- ⁇ rabbit polyclonal IgG antibody Santa Cruz Biotechnology; dilution 1 : 1 ,000
  • secondary antibodies peroxidase-conjugated AffiniPure Goat Anti-Rabbit IgG Jackson Immuno Research Laboratories, dilution
  • GAPDH (Chemicon; 1 : 10,000) was used as loading control for the cytosolic fraction.
  • a peroxidase-conjugated secondary antibody (AffiniPure Goat Anti-Mouse IgG; Jackson Immuno Research Laboratories, dilution 1 :20,000) was employed for detection.
  • In vitro PKC assay 150 ng of recombinant purified PKC isozyme (see Fig.
  • kinase assay-mix 50 ⁇ of the kinase assay-mix are added onto phosphocellulose sheets (Whatman) in a 6-well plate. The sheets were washed 3 times with 1.5% H 3 P0 4 and twice with distilled water. The phosphocellulose sheets are transferred to scintillation vials, 4 ml of scintillation fluid (Ultima Gold, Perkin-Elmer) were added and counted in a ⁇ -counter.
  • scintillation vials 4 ml of scintillation fluid (Ultima Gold, Perkin-Elmer) were added and counted in a ⁇ -counter.
  • the effect of compound 1 b (PKCe141) on the different PKC isozymes is shown in Fig. 5.
  • compound 1 b partially inhibits the cellular translocation of activated and phosphorylated PKCe to the membrane fraction.
  • PKC5 shows a high degree of homology with PKCe. Therefore, the influence of compound 1 b on PKC5 was investigated. As shown in Fig. 4, compound 1 b does not decrease PKC5 in the membrane. A similar result was obtained with immunocytochemistry (Fig. 7). Short-term treatment with TPA led to an increase of PKCe in the plasma membrane. Compound 1 b prevented the TPA-induced PKCe translocation to the plasma membrane, as shown in Fig. 7.
  • compound 1 b exhibits the features of an inhibitor of PKCe signaling in vitro and also in intact cells. A major question is whether such an inhibitor affects cell proliferation or, in other words, whether it is toxic. Therefore, compound 1 b was tested for inhibition of cell proliferation in HeLa-HLR and PC-3 cells. These cells were employed for Elk-1 phosphorylation and for the PKCe translocation experiments described above.
  • PC-3 cells were grown on glass coverslips coated with poly-L-lysine (Sigma). After treatment with compound 1 b (PKCe141 ) for 30 min and with 100 nM TPA for 5 min, the cells were rinsed twice with phosphate buffered saline (PBS) and fixed with filter sterilized 4% (w/v) paraformaldehyde/4% sucrose (w/v) (both from Sigma) in PBS at room temperature for 10 min. Subsequently the cells were washed three times with PBS and permeabilized with 0.2% Triton X-100/0.2% IgG-free BSA in PBS at room temperature for 10 min.
  • PBS phosphate buffered saline
  • sucrose w/v
  • the dish was washed with PBS to remove the cells and further incubated with 2 doxycyclin and 25 ⁇ compound 1 b (PKCe141 ) for 24 hours. Controls were left either untreated or were incubated with 2 pg/ml doxycyclin and DMSO. Migration into the scratch was observed with an Olympus microscope.
  • In vitro PKC assay 150 ng of recombinant purified PKC isozyme (see Fig. 5) were combined with 10 ⁇ 10 x kinase assay buffer (200 mM Tris-HCI , pH 7.5, 200 mM MgCI 2 ), phosphatidylserine (final 10 ⁇ ), TPA (final 1 ⁇ ) and substrate peptide RFARKGSLRQKNV (Alexis) (final 50 ⁇ ) in a volume of 100 ⁇ , 90 ⁇ l/we 11 were pipetted in a 96-well plate and incubated for 1 min at 30°C.
  • 10 ⁇ 10 x kinase assay buffer 200 mM Tris-HCI , pH 7.5, 200 mM MgCI 2
  • phosphatidylserine final 10 ⁇
  • TPA final 1 ⁇
  • substrate peptide RFARKGSLRQKNV Alexis
  • Table 2 Profile of kinase inhibition by 25 ⁇ compound 1 b (PKCe141 ). 109 different protein kinases were tested for their inhibition by compound 1 b (PKCe141 ). The five kinases inhibited most are shown in the table. All other kinases were affected less. Screening was performed by the National Centre for Protein Kinase Profiling, Division of Signal Transduction Therapy, University of Dundee. The data is portrayed as mean % activity and standard deviation (SD) of assay duplicates.
  • SD standard deviation
  • Compound 1 b (PKCe141 ), however, affected these kinases less than the PKCE/RACK2 interaction. As shown in Fig. 2A, 25 ⁇ compound 1 b (PKCe141 ) inhibited the PKCE/RACK2 interaction to approximately 10% of untreated controls, whereas 25 ⁇ of compound 1 b inhibited the most affected kinase RSK2 to 27%, as shown in Table 2 above. All other kinases were less affected. This level of selectivity is quite acceptable.
  • Example 7 Inhibition of angiogenesis Compounds according to the invention were tested for their effect on angiogenesis in vitro in a spheroid sprouting assay and in a chicken egg assay.
  • Spheroid sprouting assay (Korff et al., 1 999): Human umbilical vein endothelial (HUVEC) spheroids where generated overnight in hanging-drop culture consisting of 400 cells in EBM-2 medium, 2% FCS and 20% methylcellulose (Sigma Biochemicals). Spheroids were embedded in collagen type I from rat tail (Becton Dickinson) and stimulated with 50 ng/ml VEGF (Sigma Biochemicals) in the presence or absence of 5 ml solution containing the corresponding test compound (see Fig. 9A). Sprouts were analyzed by inverted transmission-microscopy (Zeiss Axiovert 200 M) and documented by digital imaging (Axiovision Software, Zeiss). The cumulative sprout length (CSL) was analyzed after printing of high quality pictures and counting by two independent blinded observers.
  • HUVEC Human umbilical vein endothelial
  • Chicken egg assay Eggs from hen are incubated at 37°C for 3 days, opened and incubated for further 7 days. On day ten the growth factor VEGF and compound 1 b (PKCe141 ) are added at the concentrations indicated in Fig. 9B. After further incubation for 5 days angiogenesis is observed by microscope.
  • Acetanilide (2) A solution of amine 1 (1 eq) in pyridine was cooled to 5°C and acetanhydride (1 .25 eq) was added dropwise with stirring. The mixture was stirred for 45 min at 60°C and poured into ice-water and stirred for 30 min at 0-10°C. The precipitate was filtered off, washed with water (100 ml) and dried.
  • Chloroquinolinecarbaldehyde (3) in phosphoryl chloride Dimethylformamide (9.13 g, 9.6 ml, 0.125 mol) was cooled to 0°C in a flask equipped with a drying tube and phosphoryl chloride (53.7 g, 32 2 ml, 0.35 mol) was added dropwise with stirring. To this solution was added the acetanilide 2 (0.05 mol) and after 5 min the solution was heated to 75°C for 12- 16 h. The reaction mixture was poured into ice-water (300 ml) and stirred for 30 min at 0- 10°C. The chloroquinolinecarbaldehyde 3 was filtered off, washed with water (100 ml) and dried.
  • the chloroquinolinecarbaldehyde 3 was crystallized with ethylacetate.
  • Hydroxylimine (A) Hydroxylamine hydrochloride (1 .25 eq) was added to the suspension of chloroquinolinecarbaldehyde 3 in ethanol and this mixture was refluxed for 6 h. The hydroxylimine 4 was filtered off, washed with ethanol and dried.
  • reaction mixture was poured into ice-water and stirred for 30 min at 0-10°C.
  • nitrile 5 was filtered off, washed with water and dried.
  • Raw material was purified by flash-chromatography on silica gel with chloroform and hexane (4: 1 ).
  • 2- Thio-3-cyano-quinoline (6) A mixture of 2-chloro-3-cyano-quinoline 5 (1 eq) and thiourea (3 eq) in propanol-1 was heated under reflux for 6 h, then this mixture was cooled and sodium hydroxide (10% 10 eq) was added. The reaction mixture was cooled, acidified with concentrated HCI and the solid product was filtered off and dried.
  • PLCe2024 Thieno[2,3-b]quinoline-2-carboxylanilide (PKCe2024): A mixture of the thieno[2,3- b]quinoline-2-carboxylate 8 (1 eq) and PyBOP (1 .3 eq) in DMF was stirred for 15 min, then appropriate aniline (1 .25 eq), catalytic amount of 4-dimethylaminopyridine (DMAP) and Et 3 N (2 eq) was added. The reaction mixture was stirred overnight at 50°C than it was poured into ice-water and precipitate was filtered off. Raw material was heated under reflux with methanol-DMF (3:2) and filtered off and dried.
  • DMAP 4-dimethylaminopyridine
  • the anilide PKCe2024 was purified by flash- chromatography with CHCI 3 -methanol (9: 1 ).
  • the compounds 1 m and 1 n according to the invention i.e., PKCe2023 and PKCe2024. were prepared in this manner.
  • the compounds PKCe2048 to PKCe2054 were prepared as described in Lapa et ai., 2012.
  • PKCe2053 3-Chloro-N-(7-methoxy-1 H-pyrazolo[3,4-b]quinolin-3-yl)benzamide. Yield 74%.
  • 1 H-NMR, DMSO-D6, ⁇ : 3.94 (3H, s, CH 3 ), 7.1 1 (1 H, dd, J 2.2, 9.2, H-6), 7.29 (1 H, d, J 2.2, H-8), 7.61 (1 H, t, J 8.0, H-5'), 7.71 (1 H, d, J 8.0, H-6'), 8.02 (1 H, d, J 9.2, H-5), 8.07 (1 H, d, J 8.0, H-4'), 8.17 (1 H, s, H-2'), 8.90 (1 H, s, H-4), 1 1.27 (1 H, s, NH), 13.02 (1 H, s, HN-C 0). MW Calc. for C 18 H 13 CIN 4 0 2 352.0727. Found in ESI-ms 353.0708

Abstract

La présente invention concerne de nouveaux inhibiteurs de la signalisation de la protéine kinase C epsilon (PKCε), comprenant en particulier les composés de formule (I) tels que décrits et définis ici, des compositions pharmaceutiques comportant ces inhibiteurs, et leur utilisation dans le traitement ou la prévention de troubles tels que, par exemple, trouble cardiovasculaire, hypertrophie cardiaque, insuffisance cardiaque, anxiété, douleur, douleur chronique, migraine, allergie, trouble inflammatoire, trouble auto-immuns, diabète, complications diabétiques, rétinopathie diabétique, néphropathie diabétique, cardiomyopathie diabétique, neuropathie diabétique, cancer, cancer métastatique, cancer résistant aux médicaments, cancer de l'estomac, cancer du poumon, cancer de la thyroïde, cancer du côlon, cancer du sein, trouble neurologique, maladie d'Alzheimer, maladie de Parkinson, trouble bipolaire, accident vasculaire cérébral, alopécie, ou alcoolisme.
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CN109438347A (zh) * 2018-12-19 2019-03-08 药大制药有限公司 一种氰基喹啉类ido1抑制剂、其制备方法及应用
WO2019067955A1 (fr) * 2017-09-29 2019-04-04 The Regents Of The University Of California Compositions et méthodes de régulation de cibles de micro-arn let-7
WO2019182944A1 (fr) 2018-03-23 2019-09-26 Allcron Pharma Inc. Nouveaux inhibiteurs de kinase présentant une activité anticancéreuse et leur procédé d'utilisation
WO2020080960A1 (fr) * 2018-10-19 2020-04-23 Auckland Uniservices Limited Composés pour le traitement du diabète et/ou d'états apparentés
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